Abstract
Antagonists for kainate receptors (KARs), a family of glutamategated ion channels, are efficacious in a number of animal models of neuropathologies, including epilepsy, migraine pain, and anxiety. To produce molecules with novel selectivities for kainate receptors, we generated three sets of analogs related to the natural marine convulsant neodysiherbaine (neoDH), and we characterized their pharmacological profiles. Radioligand displacement assays with recombinant α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and KARs demonstrated that functional groups at two positions on the neoDH molecule are critical pharmacological determinants; only binding to the glutamate receptor (GluR)5-2a subunit was relatively insensitive to structural modifications of the critical functional groups. NeoDH analogs in which the l-glutamate congener was disrupted by epimerization retained low affinity for GluR5-2a and GluR6a KAR subunits. Most of the analogs showed agonist activity in electrophysiological recordings from human embryonic kidney-T/17 cells expressing GluR5-2a KARs, similar to the natural convulsant neoDH. In contrast, 2,4-epi-neoDH inhibited glutamate currents evoked from both GluR5-2a and GluR6a receptor-expressing cells. Therefore, this compound represents the first compound to exhibit functional antagonist activity on GluR5-2a and GluR6a KAR subunits without concurrent activity on AMPA receptor subunits. Finally, binding affinity of the synthetic ligands for the GluR5-2a subunit closely correlated with their seizurogenic potency, strongly supporting a role for receptors containing this subunit in the convulsant reaction to KAR agonists. The analogs described here offer further insight into structural determinants of ligand selectivity for KARs and potentially represent useful pharmacological tools for studying the role of KARs in synaptic physiology and pathology.
Footnotes
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This study was supported by Kirschstein National Research Service Award F31 NS052007 (to J.M.S.), funds from the National Graduate School in Informational and Structural Biology (to P.P.), the Sigrid Jusélius Foundation (to O.T.P.), grant-in aid for scientific research awards from the Japanese Ministry of Education, Culture, Sports, Science and Technology (16073202 and 17380125 to Ma.S. and R.S., respectively), and the National Institute for Neurological Diseases and Stroke Grant R01 NS44322 (to G.T.S.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.129890.
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ABBREVIATIONS: KAR, kainate receptor; GluR, glutamate receptor; KA, kainate; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; DH, dysiherbaine; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; neoDH, neodysiherbaine; MSVIII-19, (2R,3aR,7aR)-2-[(2S)-2-qmino-2-carboxyl-ethyl]-hexahydro-furo[3,2-b]pyran-2-carboxylic acid; HEK, human embryonic kidney; iGluR, ionotropic glutamate receptor; MD, molecular dynamics; LBD, ligand binding domain; NS-102, 5-nitro-6,7,8,9-tetrahydrobenzo[g]indole-2,3-dione-3-oxime; LY377770, 3S,4aR,6S,8aR-6-(((1H-tetrazol-5-ylmethyl)oxy)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid; LY382884, 3S,4aR,6S,8aR-6-((4-carboxyphenyl)-methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
- Received August 10, 2007.
- Accepted November 20, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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